US7269308B2 - Optical waveguide type biochemical sensor chip and method of manufacturing the same - Google Patents

Optical waveguide type biochemical sensor chip and method of manufacturing the same Download PDF

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US7269308B2
US7269308B2 US11/393,771 US39377106A US7269308B2 US 7269308 B2 US7269308 B2 US 7269308B2 US 39377106 A US39377106 A US 39377106A US 7269308 B2 US7269308 B2 US 7269308B2
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optical waveguide
light beam
waveguide layer
substrate
sensor chip
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US20070081758A1 (en
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Ichiro Tono
Kayoko Oomiya
Tomohiro Takase
Ikuo Uematsu
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Toshiba Corp
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    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
    • G02B6/10—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type
    • G02B6/12—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type of the integrated circuit kind
    • G02B6/122—Basic optical elements, e.g. light-guiding paths
    • G02B6/124—Geodesic lenses or integrated gratings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N2021/7706—Reagent provision
    • G01N2021/7709—Distributed reagent, e.g. over length of guide
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/775—Indicator and selective membrane
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7783—Transmission, loss
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour

Definitions

  • the present invention relates to an optical waveguide type biochemical sensor chip and a method of manufacturing the optical waveguide type biochemical sensor chip, and particularly to an optical waveguide type biochemical sensor chip for measuring the amount and properties of the biomolecule of organisms in an aqueous solution quantitatively and to a method of manufacturing the optical waveguide type biochemical sensor chip.
  • Planar optical waveguide type biochemical sensor chips that are provided with a grating and a sensing membrane having a biomolecule recognition function and an information transformation function and utilize an evanescent wave arising on the surface of an optical waveguide layer have been proposed as small-sized and highly sensitive biochemical sensor chips.
  • a fluorescent immune sensor which has a structure in which an optical waveguide layer made of a silicon oxide film having a film thickness of 620 nm is formed on a substrate by a sol-gel method and gratings are formed on both ends of the waveguide layer.
  • an optical waveguide layer made of a silicon oxide film having a film thickness of 620 nm is formed on a substrate by a sol-gel method and gratings are formed on both ends of the waveguide layer.
  • a polyimide film may be used as the optical waveguide layer.
  • a planar optical waveguide type biochemical sensor chip which has a structure in which gratings are formed in the vicinities of both ends of a substrate and an optical waveguide layer is formed on the surface of the substrate including the gratings.
  • this optical waveguide layer is preferably a film of silicon nitride, aluminum oxide, tantalum oxide manufactured by a sputtering method or a CVD method, or a glass film manufactured by an ion exchange method.
  • An optical waveguide layer made of a similar material is disclosed in Jpn. Pat. No. 3236199.
  • Jpn. Pat. Appln. KOKAI Publication No. 2004-333250 discloses an optical waveguide sensor in which a sensing membrane having a biomolecule recognition function and an information transformation function is formed on a main surface of a glass substrate of 1 mm or less in thickness, wherein light beam is made to propagate within the substrate and to reflect on the substrate-sensing membrane interface.
  • Each of the optical waveguide layers described in the aforementioned three documents is formed in a thickness of about 1 ⁇ m depending on its material and forming method.
  • the thickness of about 1 ⁇ m is a value once to four times the thickness of the wavelength of the propagated light beam.
  • the native mode number (eigenmode) determined by each refractive index of a core layer and a clad layer and by the wavelength of incident light beam, that is, the number of incident angles enabling the light beam to be impinged with optical elements for impinging light beam, for example, the grating is a discontinuous value less than 10. It is therefore necessary to adjust the incident angle strictly corresponding to this discontinuous value.
  • light beam propagated in a planar optical waveguide layer is generally attenuated, for example, by diffusion at the interface between the optical waveguide layer and the clad layer. Accordingly, the number of reflections is increased with a decrease in the film thickness of the optical waveguide layer, resulting in a decrease in the intensity of the light beam to be emitted.
  • the number of reflections on the surface and interface (interface between the substrate and the sensing membrane) in the optical waveguide layer is increased. Therefore, the intensity of the emitting light beam attenuates and the emitting light beam tends to be affected by extraneous light beam and noise caused by, for example, the fluctuation of the system of measurement. As a result, the problem arises that a high power light source is required to obtain actual intensity of the emitted light beam, which renders it difficult to make the whole measuring system small-sized.
  • the thickness of the glass substrate is set to about 0.7 mm to 1 mm in order to propagate light beam.
  • the number of reflections on the interface between the glass substrate and the sensing membrane is decreased to a few, and detecting sensitivity is therefore lowered. If the thickness of the glass is decreased to raise the sensitivity, this reduces physical strength, bringing about handling difficulty.
  • a light source such as a laser diode
  • the optical waveguide layer In order to make it possible to utilize this light source, it is necessary to make the optical waveguide layer have a proper thickness as mentioned above and also to raise the light beam impinging and emitting efficiency.
  • light beam is diffused by, for example, scratches and contamination of optical elements such as a grating, leading to decreased coupling efficiency.
  • an optical waveguide type biochemical sensor chip comprising:
  • a light beam transmittable substrate having at least one of a first optical element which allows light beam to be impinged to the inside and a second optical element which emits light beam from the inside;
  • an optical waveguide layer which is formed on a main surface of the substrate on which at least one of the first and second optical elements is formed, has a thickness of 3 to 300 ⁇ m and is made of a polymer resin material having a higher refractive index than that of the substrate material;
  • a sensing membrane which is formed on the optical waveguide layer and creates a reaction product having the ability of absorbing light beam or an evanescent wave of light beam in response to an introduced specimen.
  • an optical waveguide type biochemical sensor chip comprising:
  • an optical waveguide layer of 3 to 300 ⁇ m in thickness by applying a polymer resin material having a higher refractive index than that of the substrate on a main surface of the substrate on which at least one of the first and second optical elements is formed, and by drying;
  • a sensing membrane which creates a reaction product having the ability of absorbing light beam or an evanescent wave of light beam in response to a specimen introduced into the optical waveguide layer.
  • an optical waveguide type biochemical sensor chip comprising:
  • an optical waveguide layer of 3 to 300 ⁇ m in thickness by applying a polymer resin material having a higher refractive index than that of the substrate on a main surface of the substrate on which at least one of the first and second optical elements is formed, and drying;
  • a sensing membrane which creates a reaction product having the ability of absorbing light beam or an evanescent wave of light beam in response to a specimen introduced into the optical waveguide layer.
  • FIG. 1 is a sectional view of an optical waveguide type biochemical sensor chip according to a first embodiment of the present invention
  • FIG. 2 is a graph showing the dependency of output intensity on the film thickness of an optical waveguide layer in the optical waveguide type biochemical sensor chip according to the first embodiment of the present invention
  • FIG. 3 is a graph showing the dependency of the ratio of a reduction in output signals on the film thickness of an optical waveguide layer in the optical waveguide type biochemical sensor chip according to the first embodiment of the present invention
  • FIG. 4 is a graph showing the dependency of the ratio of a reduction in output signals on the film thickness of an optical waveguide layer in the optical waveguide type biochemical sensor chip according to the first embodiment of the present invention
  • FIGS. 5A , 5 B, 5 C and 5 D are sectional views showing steps of producing the optical waveguide type biochemical sensor chip according to the first embodiment of the present invention
  • FIG. 6 is a sectional view of an optical waveguide type biochemical sensor chip according to a second embodiment of the present invention.
  • FIGS. 7A , 7 B, 7 C, 7 D and 7 E are sectional views showing steps of producing the optical waveguide type biochemical sensor chip according to the second embodiment of the present invention.
  • FIG. 8 is a graph showing the relationship between the concentration of glucose and the ratio of a reduction in the intensity of laser light beam (sensitivity).
  • FIG. 1 is a sectional view of an optical waveguide type biochemical sensor chip according to a first embodiment.
  • a pair of gratings 2 are formed in each region in the vicinities of both ends of a main surface of a transmittable substrate 1 made of glass (non-alkali glass) or quartz to impinge light beam into the substrate 1 and emit the light beam.
  • These gratings 2 are formed of a material (for example, titanium oxide) having a higher refractive index than the material constituting the substrate 1 .
  • An optical waveguide layer 3 is formed adjacent to the main surface of the substrate 1 on which the above grating 2 is formed, so as to be in close contact with the main surface.
  • This optical waveguide layer 3 is made of a polymer resin having a higher refractive index than the substrate 1 and has a uniform thickness designed to be in the range from 3 to 300 ⁇ m.
  • a protective film 4 is formed adjacent to the surface of the optical waveguide layer 3 so as to cover the region corresponding to each of the above gratings 2 disposed at both ends of the optical waveguide layer 3 corresponding to the region where the grating 2 is formed.
  • This protective film 4 is made of a material (for example, fluororesin) which has a lower refractive index than the material constituting the optical waveguide layer 3 and does not react with any of reagents poured into the sensor chip.
  • the sensing membrane 5 is positioned in the region sandwiched between the protective films 4 on a line connecting the gratings 2 to each other and formed adjacent to the surface of the optical waveguide layer 3 so as to be in close contact with the surface.
  • This sensing membrane 5 has a biomolecule recognition function and an information transformation function.
  • the sensing membrane 5 is specifically a film creating a reaction product having a specified concentration corresponding to a specimen having a specified concentration and introduced thereon.
  • the reaction product is of such a nature that it acts with light beam propagated in the optical waveguide type biochemical sensor chip or with an evanescent wave emitted from this light beam to consume energy, absorbs the light beam or emits fluorescent light beam.
  • the membrane body has a porous structure, and a labeled antibody that is combined with a specimen by an antigen-antibody reaction, a reagent which reacts with the label to generate a reaction product, a catalyst promoting the reaction between the label and the reagent are combined appropriately corresponding to the type of chemical and stored separately in pores formed in the porous structure.
  • a solvent of a specimen solution breaks the structure of the film to release these sensing membranes constituting materials such that these materials freely move, thereby promoting the reaction with the specimen.
  • the above sensing membrane 5 is, for example, a glucose sensing membrane, it includes a color-producing reagent, an enzyme for oxidizing or reducing glucose, a reagent which generates a substance for coloring the color-producing reagent by reacting with a product of the enzyme, a membrane forming polymer resin and, as required, a water permeable promoter such as polyethylene glycol.
  • the oxidizing enzyme, regent and color-producing reagent in the glucose sensing membrane are used in the combinations shown in the following Table 1.
  • Examples of the membrane forming polymer resin in the above glucose sensing membrane include cellulose type polymer resins such as carboxymethyl cellulose and hydroxyethyl cellulose.
  • TMBZ 3,3′,5,5′-tetramethylbenzidine
  • a specimen containing a biomolecule is brought into contact with the sensing membrane 5 of the biochemical sensor chip to extract the biomolecule from the specimen to the sensing membrane 5 .
  • This biomolecule enters into a biochemical reaction with the sensing membrane 5 .
  • a light source for example, a laser diode
  • a light beam receiving element for example, a photodiode
  • the laser light beam propagates as follows: it is refracted in the interface between the grating 2 and the optical waveguide layer 3 after passing through the substrate 1 , and refracted by the interfaces between the optical waveguide layer 3 and the substrate 1 or the sensing membrane 5 plural times.
  • the evanescent wave of the light beam propagated in the optical waveguide layer 3 is absorbed according to a change (for example, a change in absorbance) based on a biochemical reaction of the biomolecule contained in the specimen in the sensing membrane 5 , when it is refracted on the substrate-sensing membrane 5 interface.
  • a change for example, a change in absorbance
  • the light beam that has been propagated in the optical waveguide layer 3 is emitted from the backside of the substrate 1 through the right-side grating 2 and received in the photodiode 7 .
  • the intensity of the received light beam becomes a value lower than the light beam intensity (initial light beam intensity) received when the sensing membrane 5 does not enter into a biochemical reaction with the biomolecule and it is possible to detect the amount of biomolecules from the ratio of a reduction in the value.
  • optical waveguide layer 3 its thickness is designed to be in the range from 3 to 300 ⁇ m due to the following reason.
  • the intensity of incident light beam is I
  • an attenuation factor caused by the diffraction efficiency at the gratings and diffusion in places except for the inside of the optical waveguide layer is c
  • an offset component due to extraneous light beam which does not pass through the optical waveguide is ⁇
  • the intensity I (0) of emitting light beam in the state where no specimen is allowed to act on the sensing membrane is given by the following equation (1).
  • I (0) cI (1 ⁇ (0)) n + ⁇ (1)
  • FIG. 2 is a graph showing the dependency of the intensity I of output signals on the thickness of the optical waveguide layer in the first embodiment.
  • Iact and Icalc represent the actual value and calculated value of the intensity of output signals, respectively.
  • the intensity of emitted light beam is lowered as the thickness of the optical waveguide layer is decreased.
  • the ratio (R) of reduction in output signals for 180 seconds since the specimen is made to act is used as one of the indexes corresponding to concentration of the specimen to be measured.
  • FIG. 3 is a graph showing the dependency of the ratio R of reduction in output signals on the thickness of the optical waveguide layer in this embodiment.
  • Ract and Rcalc represent the actual value and calculated value of the ratio R of reduction in output signals, respectively. It is found that the ratio of reduction in output signals is not increased as the thickness of the optical waveguide layer is decreased, namely, as the number of reflections in the optical waveguide layer is increased, but takes a maximum value for the thickness of the optical waveguide layer by a reduction in the intensity (I (0)) of initial signals and by the presence of offset components.
  • Icalc and Rcalc are those described as the calculated values of the intensity of output signals and the ratio of reduction in output signals, respectively. The calculated values agreed well with the actual values.
  • FIG. 4 is a graph obtained by finding ⁇ (180) at each glucose concentration of 0.02, 0.1, 0.2, 0.5 and 5 mg/dl and using these constants to plot R as a factor of the thickness of the optical waveguide layer. It is understood from the graph of FIG. 4 that the maximum value of the ratio R of reduction in output signals is shifted to the thicker side with an increase in the concentration of glucose.
  • a calibration curve obtained by plotting the ratio R of reduction in output signals with respect to the concentration of glucose has high linearity on only the low concentration side when the thickness of the optical waveguide layer is about 10 ⁇ m or less, and it can be estimated that R at a lower glucose concentration becomes smaller (more reduced sensitivity) as the optical waveguide layer will become thicker and linearity up to a higher concentration will be improved.
  • Table 2 shows the value of the ratio R of reduction in output signals at each glucose concentration and r 2 indicating the linearity of the calibration curve in each concentration range as a factor of the thickness of the optical waveguide layer.
  • noise components background amplitude of output signals
  • R must be about 0.009 or more.
  • the linearity of the calibration curve is generally regarded as preferable when r 2 > about 0.9.
  • the thickness of the optical waveguide layer is fixed to 3 ⁇ m to 50 ⁇ m from the condition satisfying the following requirements: in a glucose concentration range from 0 to 0.2 mg/dL, R>0.09 and r 2 >0.9 when the concentration of glucose is 0.02 mg/dL.
  • an optical waveguide layer having a thickness up to about 300 ⁇ m was used based on the condition that high linearity is shown in a glucose concentration range from 0 to 5 mg/dL when the thickness of the optical waveguide layer is 50 ⁇ m or more, and the requirement R>0.09 is satisfied when the concentration of glucose is 0.1 mg/dL.
  • a restriction on the attenuation of light beam intensity and an improvement in the sensitivity of detection which are antinomic requirements caused by the thickness of the optical waveguide layer can be accomplished by setting the thickness of the optical waveguide layer to 3 to 300 ⁇ m.
  • Such a relatively thick optical waveguide layer can be attained by technologies used to apply a polymer resin solution to a substrate.
  • the thickness of the optical waveguide layer is more preferably 15 to 50 ⁇ m from the viewpoint of fulfilling the high linearity at a glucose concentration of 0 to 1 mg/dL and high detection ability indicated by R>0.009 at a glucose concentration of 0.02 mg/dL.
  • optical waveguide layer having the above thickness makes it possible to attain an optical waveguide type biochemical sensor enabling the quantitative detection of glucose having a concentration as extremely low as 0.1 mg/dL or less under the high linearity of the calibration curve.
  • the condition under which the highest coupling efficiency is obtained is given by the following equation (3), when the wavelength of the light beam to be used is ⁇ , the refractive indexes of the concave portion and convex portion of the grating are n 11 and n 12 , respectively, and the height of the grating is d.
  • ⁇ /2
  • the grating formed on the surface of the substrate is covered with the optical waveguide layer and a protective layer made of a resin having a lower refractive index than that of the optical waveguide layer is formed on the upper surface of the optical waveguide layer.
  • a protective layer made of a resin having a lower refractive index than that of the optical waveguide layer is formed on the upper surface of the optical waveguide layer.
  • the grating having a submicron size structure can be formed with high accuracy by, for example, a combination of lithographic techniques and dry etching techniques.
  • the rate of etching glass or metal oxide is by no means high and it may take several minutes to etch to a depth of 100 nm. There is therefore a fear that etching to a depth of, for example, 1 ⁇ m results in high process cost.
  • a polymer resin having a refractive index n 1 of 1.57 is used as the optical waveguide layer to allow light beam having a wavelength of 650 nm to propagate. It is therefore practical to form the grating by allowing d (height of the grating) in the above formula (3) to satisfy d ⁇ 1 ⁇ m and by forming a lattice-like pattern on a film having a refractive index n 2 meeting the relationship given by the following equation (4).
  • the length L of the optical waveguide layer (distance between the gratings) is preferably made to be shorter to reduce the attenuation factor. Since the spot diameter of laser light beam is about 0.5 to 1.0 mm, the length of the optical waveguide layer is preferably designed to be 3 mm or more and more preferably 5 to 20 mm in consideration of case of handling and alignment margin.
  • a V-parameter is known as the parameter showing propagation characteristics in a three-layer planar optical waveguide and the system is in a single mode when V ⁇ /2.
  • the thickness of the optical waveguide layer is designed to be five times or more the wavelength of the light beam to be used. As a result, it is possible to propagate light beam in a multi mode. Further, as a result of the use of diffused light beam or converged light beam as the light source, it is possible to suppress a variation in the intensity of light beam to be emitted in correspondence to a slight beam change in incident angle.
  • the aforementioned optical waveguide layer preferably has a hydrophilic functional group such as a hydroxy group, aldehyde group and carboxy group in the surface thereof.
  • the foregoing sensing membrane is satisfactorily stuck to the surface of the optical waveguide layer having such a hydrophilic functional group.
  • a film of a material for example, a titanium oxide film having a higher refractive index than that of a substrate 11 which is a transmittable plane spread like a wafer and made of non-alkali glass or quartz is formed on a main surface of the substrate 11 by sputtering.
  • the titanium oxide film formed in the above step is partially removed by lithography and dry etching so as to form a lattice pattern at a predetermined pitch, thereby forming plural gratings 12 as shown in FIG. 5A .
  • all the gratings 12 are respectively formed such that they are of the same length at the same pitch.
  • These gratings 12 allow extraneous light beam to be impinged to the inside of the optical waveguide layer and allow the light beam to emit externally (to the substrate side) when the light beam propagated in the optical waveguide layer reaches the gratings 12 .
  • a polymer resin material that has a higher reflectance than that of the material constituting the transmittable substrate 11 and is likewise transmittable is applied to the entire surface of the principal plane of the transmittable substrate 11 on which the gratings 12 are formed in a uniform film thickness by a spin coater and dried, to thereby form an optical waveguide layer film 13 made of polymer resin material and having a thickness of 3 to 300 ⁇ m.
  • a material for example, a fluororesin material, that has a lower refractive index than that of the material constituting the optical waveguide layer and does not react with a reagent is formed on the surface part of the optical waveguide layer 13 which corresponds to the region in which the grating 12 is formed by screen printing and dried to form a protective film 14 .
  • the operations are carried out such that the protective film is not formed on the region where the sensing membrane is to be formed. This ensures that the protective film 14 is a film having a frame structure enclosing the region where the sensing membrane is to be formed.
  • the optical waveguide layer 13 and the protective film 14 are washed. Specifically, the surfaces of the optical waveguide layer 13 and protective film 14 are irradiated with excimer ultraviolet light beam (for example, a wavelength of 172 nm), then dipped in an alkaline solution and washed with pure water. Since impurities such as a fluororesin exist on the surface of the region unprotected with the protective film, they are removed. Then, the substrate 11 is cut up into pieces to form chips by dicing. At this time, the region where the sensing membrane is to be formed and the pair of gratings 12 disposed to sandwich this region are combined as a unit and the substrate 11 is cut up into pieces such that this unit of the structural elements remains in each piece.
  • excimer ultraviolet light beam for example, a wavelength of 172 nm
  • the membrane-forming coating solution described in the aforementioned Table 1 is dripped on the region (region where the sensing membrane is to be formed) where the protective film 14 is not formed.
  • the coating solution is dried to form a sensing membrane 15 in the region which is positioned between the gratings 12 and in which the protective film 14 is not formed as shown in FIG. 5D .
  • the optical waveguide type biochemical sensor chip is completed.
  • a planar optical waveguide type biochemical sensor chip can be obtained in which the measuring system can be small-sized and which makes it simple to carry out an operation of measuring a specimen.
  • a restriction on the attenuation of light beam intensity and an improvement in the sensitivity of detection which are antinomic requirements can be accomplished by setting the thickness of the optical waveguide layer to 3 to 300 ⁇ m
  • the optical waveguide layer having such a thickness can secure sufficient transmittance. Also, the formation of the grating using a material having a refractive index higher by 0.3 or more than that of the optical waveguide layer has succeeded in obtaining high diffraction efficiency even when it has a height as low as 1 ⁇ m or less. These characteristics make it possible to use a small-sized and inexpensive laser diode having a relatively low power as a light source.
  • the grating is formed on the surface of the substrate and covered with the optical waveguide layer, and the part of the surface of the optical waveguide layer which is positioned above the grating is coated with a material having a refractive index lower than that of the optical waveguide layer, which ensures that damages and contaminations to the coupling function elements can be suppressed.
  • the thickness of the optical waveguide layer is designed to be five times or more the wavelength of the light source to be used, which has brought about the situation where waveguide light beam is propagated in a multi-mode in the optical waveguide layer.
  • the use of diffused light beam or converged light beam as the light source has brought about the situation where it is possible to suppress a variation in the intensity of light beam to be emitted in correspondence to a slight beam change in incident angle.
  • FIG. 6 is a sectional view of an optical waveguide type biochemical sensor chip according to a second embodiment.
  • a pair of gratings 12 are formed in each region in the vicinities of both ends of a main surface of a substrate 11 made of glass (for example, non-alkali glass) or quartz to impinge light beam into the substrate 11 and emit the light beam.
  • These gratings 12 are formed of a material, for example, titanium oxide, having a higher reflectance than that of the substrate 11 .
  • An optical waveguide layer 13 which is formed of a polymer resin having a higher refractive index than that of the substrate 11 and has a thickness of 3 to 300 ⁇ m is formed on the main surface of the substrate 11 including the above gratings 12 .
  • a protective film 14 made of a material (for example, a fluororesin) which has a low refractive index and does not react with a regent is formed in each vicinity of both ends of the optical waveguide layer 13 which corresponds to the grating 12 , i.e., positions corresponding to the grating 12 .
  • a sensing membrane 15 having a biomolecule recognition function and an information transformation function is formed on the part positioned between the protective films 14 on the optical waveguide layer 13 .
  • a polymer resin layer 16 having the same material and the same thickness as the above optical waveguide layer 3 is formed on the entire surface of the backside of the substrate 11 , that is, the main surface on the side of the substrate 11 on which the optical waveguide layer 13 is not formed such that it is stuck to and disposed adjacent to the backside surface.
  • Such an optical waveguide type biochemical sensor chip according to the second embodiment can detect the quantity of biomolecules in a specimen in the same operation as in the case of the sensor chip shown in the first embodiment. Also, the optical waveguide type biochemical sensor can limit the warpage thereof caused by extraneous factors such as a variation in temperature by using a simple structure, enabling the formation of a measuring system structure resistance to disturbances.
  • the thickness range of the optical waveguide layer is limited to 3 to 300 ⁇ m, for the same as reason as that explained in the first embodiment.
  • the thickness of the optical waveguide layer is more preferably 15 to 50 ⁇ m.
  • the length (length of the interval between the gratings) of the optical waveguide layer is preferably 3 mm or more and more preferably 5 to 20 mm.
  • the aforementioned optical waveguide layer preferably has a hydrophilic functional group such as a hydroxy group, aldehyde group and carboxy group in the surface thereof.
  • the foregoing sensing membrane is satisfactorily stuck to the surface of the optical waveguide layer having such a hydrophilic functional group.
  • the above sensing membrane is, for example, a glucose sensing membrane
  • it includes a color-producing reagent, an enzyme for oxidizing or reducing glucose, a reagent which generates a substance for coloring the color-producing reagent by reacting with a product of the enzyme, membrane forming polymer resin (cellulose type polymer resins such as carboxymethyl cellulose and hydroxycellulose) and, as required, a water permeable promoter such as polyethylene glycol.
  • the color-producing reagent, oxidizing enzyme and regent in the glucose sensing membrane are used in the combinations shown in the aforementioned Table 1.
  • a film of a material (for example, a titanium oxide film) having a higher refractive index than that of a substrate 11 made of non-alkali glass or quartz is formed on the principal plane of the substrate 11 by sputtering as shown in FIG. 7A .
  • the titanium oxide film is selectively removed by lithography and dry etching to form a grating 12 .
  • a main surface of the substrate 11 including the grating 12 is coated with a resist film 21 that protects the grating 2 .
  • the substrate 11 is turned over and a solution of a polymer resin having a higher refractive index than that of the substrate 11 is applied to the backside of the substrate 11 and dried, thereby forming a polymer resin layer 16 having a thickness of 3 to 300 ⁇ m as shown in FIG. 7B .
  • a solution of a polymer resin having the same material as the above polymer resin is applied to the entire surface of the substrate 11 including the grating 12 by spin coating or the like and dried, thereby forming an optical waveguide layer 13 having the same thickness as that of the polymer resin layer 16 as shown in FIG. 7C .
  • a material such as a fluororesin material, which has a low refractive index and does not react with a reagent is formed on the surface part of the optical waveguide layer 13 which corresponds to the grating 12 by screen printing and dried, thereby forming a protective film 14 as shown in FIG. 7D .
  • this substrate 11 is cut into chips by dicing.
  • impurities such as a fluororesin exist on the surface of the region which is positioned between the protective films and in which the sensing membrane is to be formed, on the optical waveguide layer. Therefore, the substrate 11 is irradiated with excimer ultraviolet light beam having a wavelength of, for example, 172 nm, then dipped in an alkaline solution and washed with pure water.
  • a membrane-forming coating solution having the components described in the aforementioned Table 1 is dripped on the region which is positioned between the protective films 14 on the surface of the optical waveguide layer 13 and dried, thereby forming a sensing membrane 15 in the region which is positioned between the gratings and in which the protective film is not formed as shown in FIG. 7E .
  • the optical waveguide type biochemical sensor chip according to the second embodiment is completed.
  • the thickness of the optical waveguide layer is limited to a range from 3 to 300 ⁇ m, whereby the incident angle at which light beam can be impinged with the grating for impinging light beam in the first embodiment can be broadened and an optical waveguide type biochemical sensor chip that detects microorganisms by simple operations can be obtained.
  • the thickness of the optical waveguide layer 3 to 300 ⁇ m.
  • the optical waveguide layer having such a thickness ensures satisfactory transmittance. It is therefore possible to use a small-sized and inexpensive laser diode having a relatively low power as a light source.
  • the formation of the polymer resin layer 16 having the same material and the same thickness as those of the optical waveguide layer 13 on the backside of the substrate 11 makes the substrate 11 resistant to warpage, thereby allowing light beam to be impinged to the substrate at a regular angle.
  • the optical waveguide layer 13 made of a polymer resin and having a thickness as relatively high as 3 to 300 ⁇ m is formed on a substrate such as glass
  • a substrate such as glass
  • the difference in these coefficients of linear expansion causes warpage of the substrate 1 in the case where the biochemical sensor chip is heated.
  • the occurrence of warpage of the substrate 11 would cause a fluctuation in the incident angle of the substrate 11 , with the result that the sensitivity of detection is reduced.
  • the polymer resin layer 16 having the same material and the same thickness as those of the optical waveguide layer 13 is formed on the backside of the substrate 11 .
  • This enables the prevention of warpage of the substrate 11 because a warpage caused by the difference in the coefficients of linear expansion between the substrate 11 and the optical waveguide layer 13 can be offset by the stress imposed in the opposite direction in the same amount of warpage caused by a difference in the coefficients of linear expansion between the substrate 11 and the polymer resin layer 16 formed on the backside of the substrate 11 .
  • light beam can be impinged to the substrate 11 at a regular angle, and it is therefore possible to maintain a high detection sensitivity.
  • the method according to the second embodiment ensures that the optical waveguide type biochemical sensor chip having the aforementioned excellent characteristics can be manufactured.
  • the polymer resin layer 16 is formed on the backside of the substrate 11 just after the grating 12 is formed, namely, before the optical waveguide layer 13 is formed, whereby damage to the optical waveguide layer 13 can be prevented.
  • the grating 12 is covered with the easily removable resist film 21 . It is therefore possible to protect the grating 12 during spin coating for forming the polymer resin layer 16 .
  • a titanium oxide film of 50 nm in thickness was formed on a principal plane of a non-alkali glass substrate having a refractive index of 1.52 by sputtering titanium oxide having a refractive index of 2.2 to 2.4. Then, the titanium oxide film was selectively removed by lithography and dry etching (RIE) to form a grating.
  • RIE lithography and dry etching
  • a heat-curable resin solution was applied to the principal plane of the glass substrate including the grating by a spin coater and baked to form an optical waveguide layer having a thickness of 25 to 35 ⁇ m and a refractive index of 1.57.
  • a fluororesin was formed on the surface part of the optical waveguide layer which corresponded to the grating by screen printing and dried to form a protective layer.
  • the substrate was cut into pieces having the dimensions of 17 mm ⁇ 6.5 mm to make chips.
  • the region of the optical waveguide layer which was positioned between the protective films was irradiated with excimer ultraviolet light beam having a wavelength of 172 nm, then dipped in an alkaline solution and washed with pure water to provide moderate hydrophilic properties.
  • a glucose sensing membrane-forming coating solution was dripped on the surface of the sensing membrane-forming region positioned between the gratings of the substrate, followed by purging using inert gas and drying under vacuum to form a porous (water permeable) glucose sensing membrane of 0.5 to 1.0 ⁇ m in thickness, and the optical waveguide type biochemical glucose sensor shown in FIG. 1 was thus produced.
  • the glucose sensing membrane-forming coating solution had the following composition.
  • a laser diode 6 and a photodiode 7 were disposed on the left and right sides of the backside of the substrate 1 of the biochemical glucose sensor, respectively.
  • the laser light beam having a wavelength of 655 nm was allowed to be impinged to the left side grating 2 from the laser diode 6 , propagated in an optical waveguide layer 3 and emitted from the right side grating 2 .
  • a fixed amount of an aqueous glucose solution was dripped on the sensing membrane 5 while measuring the intensity of the light beam by the photodiode 7 .
  • the ratio of reduction (sensitivity) in the intensity of laser light beam for a fixed time after the glucose solution was dripped was plotted as a factor of the concentration of glucose. The results are shown in FIG. 8 .
  • the glucose sensor chip of Example 1 can detect glucose having a low concentration with a high sensitivity.
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